1. Field of the Invention
The present invention relates to the use of 99mTc(V)-dimercaptosuccinic acid for detecting cancerous bone metastasis of the osteoclastic or mixed type by means of bone scintigraphy, and facilitating selection of a therapy for the cancerous bone metastasis.
2. Description of Related Art Including Information Disclosed under 37 CFR 1.97 and 1.98
Whether cancerous bone metastasis has occurred is an important factor that affects prognosis, and also influences the therapeutic plan for the primary lesion. Furthermore, since options of therapies for bone metastasis and accompanying symptoms are increasing, diagnosis of presence or absence, or spread of bone metastasis plays an important role in deciding a therapeutic plan. Bone metastasis can be seen more or less in every cancer. The diagnosis of bone metastasis would be of particular importance in breast cancer, prostatic cancer, lung cancer, thyroid cancer and renal cancer since these cancers are generally considered higher in risk of bone metastasis than other cancers.
Bone metastasis can be pathologically classified into four types: osteoblastic type, osteoclastic type, mixed type in which the aforementioned two types are mixed together, and inter-trabecular type in which neither osteoblastic nature nor osteoclastic nature is exhibited. Among the cancers high in the risk of bone metastasis, it is likely that prostatic cancer causes the osteoblastic type, renal cancer and thyroid cancer causes the osteoclastic type, lung cancer causes both the osteoclastic and the mixed types, and breast cancer causes the mixed type. Among the four types, the osteoclastic type is characterized by bone resorption due to growth of osteoclastic cells, and is likely to result in bone fracture. For this reason, the osteoclastic type of bone metastasis is said to have a significantly higher incidence of pains than other types. Among the patients of breast cancer with bone metastasis, it is said that patients of the osteoblastic type survive the longest, being followed by patients of mixed type and osteoclastic type, in this order. So, the identification of metastasis type is also considered important.
Bone scintigraphy is generally used to examine the presence or absence of bone metastasis in cancer patients. Usually, a 99mTc-labelled bisphosphonate (99mTc-BP) such as 99mTc-MDP (methylene diphosphonate), 99mTc-EHDP (ethane hydroxy-diphosphonate) or 99mTc-HMDP (hydroxymethylene diphosphonate) is intravenously injected as a diagnostic imaging agent, and then scintigrams are taken. Mechanism of bone accumulation of the 99mTc-BP is still unclear, but it is found that the 99mTc-BP highly accumulates in osteoblastic lesions. So, the 99mTc-BP is useful for detecting the osteoblastic type bone metastasis. However, the 99mTc-BP does not appear to depict lesions of osteoclastic type bone metastasis as positive images, and this is a problem.
On the other hand, as for 99mTc-dimercaptosuccinic acid (99mTc-DMS), the trivalent 99mTc-DMS is well known as a diagnostic imaging agent for kidney, while pentavalent 99mTc(V)-DMS is reported to accumulate in tumor lesions such as of thyroid carcinoma (MTC), osteosarcoma, and benign and malignant tumors of various soft tissues. JP-A-56-7725 proposes the use of 99mTc(V)-DMS as a tumor scanning agent. Furthermore, it is also reported that 99mTc(V)-DMS depicts lesions of bone metastasis caused by various cancers as positive images.
As described above, 99mTc(V)-DMS is a polynuclear complex having a nature of accumulating in both cancers and bones. The accumulation in cancers is presumed to depend on pH values, but no mechanism of the accumulation in bones has been known even though there are clinical reports that the 99mTc(V)-DMS would accumulate in lesions of osteoclastic type metastasis.
Meanwhile, bone fractures involved in the bone metastasis of tumors are considered to include those caused directly by protease secreted from tumor cells and those caused by way of activated osteoclast. In recent years, it has been clarified that bone resorption is inhibited by bisphosphonate compounds such as pamidronate, clodronate, etidronate, tiludronate and alendronate, and that these compounds would be effective for preventing bone fractures associated with osteoporosis and tumorous bone metastasis. Mechanism of the inhibitory action on bone resorption has not yet been sufficiently clarified, but it is said that the inhibitory action results from bisphosphonate compounds that act directly or indirectly on osteoclast, thereby inactivating and decreasing osteoclast. Therefore, if any diagnostic method using any compound specifically taken up by osteoclast is established, it will become possible to accurately select patients who are suited to therapy targeted at osteoclast by use of the recently developed bisphosphonate compounds.
Under the above-mentioned circumstances, the object of present invention is to allow a precise diagnostic imaging of cancerous osteoclastic type or mixed type bone metastasis using a compound capable of being specifically taken up by osteoclast, thereby enabling an appropriate selection of a therapy based on the diagnosis.
In order to achieve the above-mentioned object, the inventors have intensively studied on the mechanism of 99mTc(V)-DMS accumulation in the lesions of bone metastasis, and as a result, have found that while the 99mTc-BP used as a conventional diagnostic imaging agent is remarkably taken up by osteoblast but is hardly taken up by osteoclast, 99mTc(V)-DMS shows the following characters (1)-(5): (1) 99mTc(V)-DMS is less taken up by osteoblast than 99mTc-BP, but is taken up by osteoclast in an especially large amount. (2) The amount of the 99mTc(V)-DMS taken up by osteoclast remarkably increases at low pH values. (3) The phenomenon of the above (2) is presumed to have relation with activation of function of the osteoclast in an acidic environment. (4) 99mTc(V)-DMS shows a behavior similar to phosphate anion when taken up by osteoclast, and it is taken up by osteoclast through Na+-dependent phosphate transporter that relates to the transport of inorganic phosphate to osteoclast. (5) 99mTc(V)-DMS shows a distribution in vivo that corresponds to the distribution of osteoclast, and thus is preferentially taken up by osteoclast rather than osteoblast. On the basis of these evidences, the present invention has been completed.
According to the present invention, provided is a diagnostic imaging agent useful for selecting a therapy for cancerous bone metastasis, comprising 99mTc(V)-dimercaptosuccinic acid as an effective ingredient. Cancerous bone metastases include those of the osteoclastic or mixed type which accompanies localization and activity rise of osteoclast, and those of the osteoblastic or inter-trabecular type which is considered to receive no or little contribution of osteoclast. Since 99mTc(V)-dimercaptosuccinic acid is highly specific to osteoclast, it allows the osteoclastic type or mixed type bone metastasis to be accurately identified, and facilitates the decision as to whether or not a therapy targeted at osteoclast should be applied.
There is no limitation in kinds of the therapy targeted at osteoclast as long as they are expected to give a therapeutic effect in a way that directly or indirectly acts on osteoclast and thereby inhibits bone resorption or palliates bone pain. Typically, such a therapy includes one using a bisphosphonate compound.
The bisphosphonate compound means germinal bisphosphonates having a P-C-P skeleton structure, and includes many therapeutic agents that are commercially available or clinically being developed, such as etidronate, clodronate, pamidronate, alendronate, ibandronate, incadronate, olpadronate, zoledronate, tiludronate, neridronate, risedronate, YH592 and EB-1053.
Besides, a therapy is practiced in which 89SrCl2 or another compound having affinity with bones is intravenously administered, and then a lesion of a cancerous bone metastasis is irradiated in vivo in order to efficiently palliate the pain involved in the bone metastasis. While 89SrCl2 can highly accumulate in lesions of osteoblastic type bone metastasis, it is predicted that 186Re or 188Re-labeled dimercaptosuccinic acid attempted for clinical application similarly to 89SrCl2 can highly accumulate in lesions of osteoclastic type or mixed type bone metastasis where osteoclast is localized. Therefore, the present diagnostic imaging using 99mTc(V)-DMS is useful for the selection of these bone pain palliation agents.
According to another aspect of the present invention, there is provided a method of diagnosis for localization of osteoclast, which comprises administering a patient with a diagnostic imaging agent that contains 99mTc(V)-dimercaptosuccinic acid as an effective ingredient, and then taking a scintigram, whereby osteoclast are located.
Diagnosis for scrutinizing the localization of osteoclast can be applied to the diseases in which bone resorption caused by osteoclast increases, and the diseases typically covered by the diagnosis are osteoporosis and osteoclastic type or mixed type cancerous bone metastases.
In both cases of the above selection of therapy and the above diagnosis of localization, the diagnostic imaging agent containing 99mTc(V)-dimercaptosuccinic acid as an active ingredient can be used alone to achieve the object, but it may also be used in combination with a diagnostic agent containing 99Tc-BP so as to more accurately evaluate participation of osteoclast.
The 99mTc(V)-dimercaptosuccinic acid used in the present invention can be obtained by mixing a 99mTc pertechnetate solution with a solution that contains dimercaptosuccinic acid and a reducing agent such as stannous chloride with adjustment to alkaline pH using a sodium hydrogen carbonate buffer or the like. For example, as disclosed in H. Kobayashi et al., Eur. J. Nuc. Med. 22: 559-562 (1995), it can readily be produced by adding a sodium hydrogen carbonate buffer to a commercially available renal scintigraphic preparation (99mTc (III)-DMS) kit for adjustment to alkaline pH, and then mixing the resultant solution with a 99mTc pertechnetate solution. In this instance, a small amount of oxygen may be allowed to oxidize 99mTc(III)-DMS and excessive stannous chloride so that radiochemical purity is improved. However, drugs should be prepared using a special kit for it, and for this purpose, a labeling kit specifically designed for 99mTc(V)-DMS disclosed in I. Yomoda et al., Jpn. J. Nucl. Med. (Kaku Igaku), 24: 77-82 (1987) is available. This kit has dimercaptosuccinic acid, stannous chloride and others contained as freeze-dried in a sealed vial, and 99mTc(V)-DMS can be prepared by adding a 99mTc pertechnetate solution containing a small amount of sodium hydrogen carbonate buffer to the vial.
Usually, the thus-produced 99mTc(V)-DMS preparation is intravenously administered by 100 MBq to 1500 MBq, preferably 200 MBq to 1000 MBq, more preferably 350 MBq to 750 MBq. The dosage may be varied depending upon the weight and the like of a patient.
Within a period of 30 minutes to five hours, preferably 1 hour to 4 hours, more preferably 2 hours 3 hours after administration, anterior and posterior images or divisional images of the whole body, and as required, spot images or tomograms (single-photon-emission computed tomographic (SPECT) images) of specific regions are taken as scintigrams. Based on the thus-obtained scintigrams, diagnosis and appropriate selection of therapy can be made.
According to the present invention, the presence or absence of active osteoclast or osteoclastic lesions can be identified, and thus it becomes possible to accurately determine the applicability of therapies targeted at osteoclast. For this reasons, misdirected therapies will decrease, and a great advantage in terms of medical economy will be provided. Also, patient""s choices of effective therapies will increase, and in turn the risk of losing chances of receiving effective therapies due to sustained application of ineffective therapies will decrease.